The Role of Pharmacogenetics in Precision Medicine
Clinicians have long been aware that patients do not uniformly respond to medications.
Clinicians have long been aware that patients do not uniformly respond to medications. In some patients, one drug may not be as effective as expected, whereas in other patients, it may cause adverse reactions, sometimes life-threatening. The causes of these variations in drug response include clinical, environmental, and genetic factors. Pharmacogenetics is the study of genetic causes of individual variations in drug response. It is a hybrid between pharmacology (the science of drugs) and genetics (the science of genes and their action).
The term “pharmacogenetics” was first coined by Friedrich Vogel in 1959.1 Then, in the late 1990s, with advancements in DNA technology and modern genomic sciences, a newer term—“pharmacogenomics”— was introduced. Both terms are used interchangeably, with pharmacogenetics normally referring to the study of individual gene—drug interactions (usually 1 or 2 genes that have a dominant effect on a drug response). Pharmacogenomics, however, is a broader term for the study of genomic influence on drug response, often using high-throughput approaches such as sequencing, single nucleotide polymorphism chip, expression profiling, and proteomics. These findings can then be used to predict how a patient may react to a medication, from both the safety and efficacy standpoints. Pharmacogenetics is a core element of precision medicine.
HISTORY OF PHARMACOGENETICS
The earliest documentation of pharmacogenetics dates back to 510 BC, when Pythagoras noted that a subset of people ingesting fava beans experienced potentially fatal hemolytic anemia, whereas others did not.2 This was later found to be due to an inherited deficiency of glucose-6-phosphate dehydrogenase in individuals with fatal reaction to fava beans.
Since the beginning of the 20th century, many landmark discoveries in pharmacogenetics have been made in terms of the evolution of human genetics and molecular pharmacology that have shaped our current understanding and approaches.3 In 1909, British physician Archibald Garrod developed the concept of “chemical individuality,” a phenomenon he summarized in The Inborn Errors of Metabolism as follows: “Every active drug is a poison, when taken in large enough doses; and in some subjects, a dose which is innocuous to the majority of people has toxic effects, whereas others show exceptional tolerance of the same drug.”4
In the 1950s, pharmacogenetics emerged as a distinct discipline, with 3 landmark discoveries clearly demonstrating genetically determined variations in enzyme activity underlying the causes of adverse drug reactions. Bönicke et al described slow and rapid acetylation of isoniazid in 1953,5 which was found, 40 years later, to be due to mutations in N-acetyltransferase-2. Then in 1956, Alving et al discovered the association of primaquine-induced hemolysis with glucose-6-phosphatedehydrogenase deficiency that altered erythrocyte metabolism.6 This was followed in 1957 by Kalow et al, who characterized serum-cholinesterase deficiency in a subject with succinylcholine apnea.7 That same year, Arno Motulsky was the first to recognize the significance of these key discoveries, and he further refined the concept that inherited “gene-controlled enzymatic factors” may explain individual differences in drug response.8 These discoveries triggered many family studies over the following years, documenting the patterns of inheritance associated with drug effects, eventually leading to discoveries of many genetic determinants for these traits.
The first polymorphic human drug metabolizing gene, Cytochrome P450 family 2 subfamily D member 6 (CYP2D6), was cloned and characterized in 1987. Subsequently, polymorphisms in various phase 1 and phase 2 drug metabolizing enzymes and drug transporters were identified and associated with various drug response traits.9-11 With the completion of the first draft of the human genome,12,13 more evidence emerged from genomewide and candidate gene studies, leading to the identification of genetic factors modulating the responses and toxicities of hundreds of drugs.
Evidence of the clinical utility of pharmacogenomics has also been accumulating.14 As of May 2016, 30 published gene—drug pair Clinical Pharmacogenetics Implementation Consortium (CPIC; cpicpgx.org) guidelines, in which a particular gene variation has implications for how a patient will respond to a given drug, have been documented, along with clinical dosing guidelines.15 A more comprehensive catalog of human genetic variation—associated drug responses (eg, ~200 clinically actionable drug-gene pairs) can be obtained through the Pharmacogenomics Knowledge Base (pharmgkb.org).16
The goal of pharmacogenomics in the clinical setting is straightforward: to maximize drug efficacy and minimize the likelihood of adverse drug reactions. The potential clinical benefits of pharmacogenomics are immense. Currently, drug therapy in medicines is still mostly practiced by empirical selection of drugs. Their efficacy may vary widely, and adverse events are common and unpredictable. It is clear that the one-size-fits-all model is not ideal for effective treatment of patients. With accurate and reliable pharmacogenomic information in hand at the point of prescribing, physicians will be able to prescribe medicines that provide the optimal safety and efficacy profile for an individual patient.
With genotype-guided drug and dose selection, we can better target those most likely to benefit and least likely to be harmed, ultimately leading to reduced overall health care costs and improved patient outcomes. For example, Plavix (clopidogrel), one of the most frequently prescribed antiplatelet agents, requires bioactivation mediated by CYP2C19. Research shows that patients carrying a CYP2C19 loss-of-function allele have a decreased response to clopidogrel and an increased incidence of major adverse cardiac events and stent thrombosis compared with noncarriers.17 Currently, there is strong evidence supporting CYP2C19 genotyping in patients with acute coronary syndrome undergoing percutaneous coronary intervention. The dosing recommendation based on interpretation of the CYP2C19 genotype for clopidogrel is also clearly outlined in the CPIC guideline.18
Recognizing the growing need for pharmacogenetics information and guidance from the clinical community, the FDA started incorporating pharmacogenetics information into drug labels and now offers a list of drugs for which biomarkers are included in the labeling. Some labels contain actions that can be taken based on the biomarkers; many do not. In addition, a growing number of institutions are beginning to develop clinical services and infrastructures supporting pharmacogenetics testing.
In January 2015, President Obama launched the Precision Medicine Initiative as “an innovative approach to disease prevention and treatment that takes into account individual differences in people’s genes, environments, and lifestyles”.19 Pharmacogenomics represents one of the most practical applications of precision medicine. Despite challenges involved in bringing pharmacogenetics testing into the clinic, we are starting to see the paradigm shift from whether to order a genetic test to how to use the genetic test results already in the system for prescribing decisions.
Because of their expertise in clinical pharmacology and patient care, pharmacists have a unique role in incorporating pharmacogenomics into the practice of medication therapy management.20 It is therefore important for pharmacists to be knowledgeable in the rapidly expanding fields of pharmacogenomics and to take a prominent role in its clinical application.
Sources of funding: NIH/NIGMS R24 GM61374 and R24 GM115264. Dr. Teri E. Klein and Dr. Michelle Whirl-Carrillo are paid scientific advisors to the Rxight Pharmacogenetic Program.
Li Gong, PhD; Michelle Whirl-Carrillo, PhD; and Teri E. Klein, PhD, work at the Department of Genetics, Stanford University, Stanford, California. In addition, Li Gong is a scientific curator at PharmGKB; Michelle Whirl-Carrillo is the associate director of PharmGKB; and Teri E. Klein is the coprinicipal investigator and director of PharmGKB, and the coprinicipal investigator of the Clinical Pharmacogenetics Implementation Consortium.
- Vogel F. Moderne probleme der Humangenetik. Ergeb Inn Med Kinderheild. 1959;12:52-125.
- Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin Genet. 1999;56(4):247-258.
- Meyer UA. Pharmacogenetics - five decades of therapeutic lessons from genetic diversity. Nat Rev Genet. 2004;5(9):669-676.
- Garrod AE. Inborn Errors of Metabolism. New York, NY: Oxford University Press; 1909.
- Bonicke R, Reif W. Enzymatic inactivation of isonicotinic acid hydrizide in human and animal organism. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1953;220(4):321-323.
- Alving AS, et al. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science. 1956;124(3220):484-485.
- Kalow W, Staron N. On distribution and inheritance of atypical forms of human serum cholinesterase, as indicated by dibucaine numbers. Can J Biochem Physiol. 1957;35(12):1305-1320.
- Motulsky AG. Drug reactions, enzymes, and biochemical genetics. JAMA. 1957;165(7):835-837.
- Gonzalez FJ, Skoda RC, Kimura S, et al. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature. 1988;331(6155):442-446.
- Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol. 1979;16(3):183-187.
- Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of debrisoquine in man. Lancet. 1977;2(8038):584-586.
- Lander, ES, Linton LM, Birren B, et al; International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860-921. doi:10.1038/35057062.
- Venter JC, Adams MD, Myers EW, et al [erratum appears in Science. 2001;292(5523):1838]. The sequence of the human genome. Science. 2001;291(5507):1304-1351. doi: 10.1126/science.1058040.
- Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature. 2015;526(7573):343-350. doi: 10.1038/nature15817.
- Relling MV, Klein TE. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clin Pharmacol Ther. 2011;89(3):464-467. doi: 10.1038/clpt.2010.279.
- Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414-417. doi: 10.1038/clpt.2012.96.
- Shuldiner AR, O’Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302(8):849-857. doi: 10.1001/jama.2009.1232.
- Scott, SA, Sangkuhl K, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317-323. doi: 10.1038/clpt.2013.105.
- Fact Sheet: President Obama’s Precision Medicine Initiative. The White House Office of the Press Secretary website. whitehouse.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative2015. Published January 30, 2015. Accessed June 3, 2016.
- ASHP statement on the pharmacist's role in clinical pharmacogenomics. Am J Health Syst Pharm, 2015;72(7):579-581. doi: 10.2146/sp150003.